Pharmaceutical composition based on micronized progesterone, preparation method and uses thereof

ABSTRACT

The present invention relates to a pharmaceutical composition comprising micronized progesterone, soya bean lecithin, and at least one oil selected from the group consisting of sunflower oil, olive oil, sesame seed oil, colza oil, almond oil, to the method for the preparation thereof and to the uses thereof for treating a physiological condition linked to insufficiency of progesterone secretion.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/495,242, filed May 6, 2004, which is the U.S. National Stage ofPCT/FR02/03879, filed Nov. 13, 2002, the entire contents of which areincorporated herein by reference in its entirety. The application alsoclaims priority to FR 01/14653, filed Nov. 13, 2001.

BACKGROUND

The present invention relates to a pharmaceutical composition containingmicronized progesterone, soya bean lecithin, and at least one oilselected from the group consisting of sunflower oil, olive oil, sesameseed oil, colza oil and almond oil. It also relates to pharmaceuticalproducts comprising said pharmaceutical composition.

The invention also relates to the method for manufacturing thispharmaceutical composition, as well as to the uses thereof.

Progesterone is a hormone which is synthesized, in women, essentially bythe ovary during the postovulation or luteal phase (more precisely bythe cells of the corpus luteum) and, to a lesser degree, by the adrenalglands and the placenta during the second part of pregnancy.Non-endocrine synthesis of progesterone, in particular in neurons, isalso possible.

A consequence of insufficiency of progesterone secretion in a woman is aloss of its biological effects: progestative effect, anti-androgeneffect (action on the skin) and anti-oestrogen effect (the consequencebeing hyperoestrogenemia: hot flushes, psychogenic difficulties of theanxious or depressive type, weight gain, etc.). This progesteroneinsufficiency may lead to functional difficulties and diverse clinicalmanifestations, in particular:

-   -   premenstrual syndromes,    -   menstrual irregularities due to disovulation or anovulation,    -   benign mastopathies,    -   perimenopause and menopause.

However, oral administration of progesterone suffers from a serioushandicap due to the poor intestinal absorption and to the intensehepatic metabolism (short plasmatic half-life) of this hormone. Only thevaginal, rectal and intramuscular pathways would, to date, make itpossible to maintain blood progesterone level at the physiological levelof the luteal phase, for several hours.

The LABORATOIRES BESINS-ISCOVESCO have already proposed a solution inorder to improve the quality and intensity of the digestive absorptionof natural progesterone, in Patent Application FR 76 36007.Specifically, they have developed a formulation of soft capsulescontaining micronized progesterone in oily suspension. The synergisticeffect of the micronization and the use of molecules containinglong-chain fatty acids has made it possible to indisputably increase thebioavailability of progesterone taken orally. This formulation has knowna great deal of success worldwide. It is sold in France under the trademark UTROGESTAN®.

The oil which serves as a basis for the oily suspension in UTROGESTAN®is peanut oil.

Peanut (Arachis hypogae) is a leguminous plant, a bushy annual plantwith yellow flowers, of the Papilionacea family.

In the last 15 years, peanut allergy has become a considerableallergological problem.

Dutau et al. (La Presse Médicale [Medical Press], vol. 28, p. 1553)observe that the prevalence of peanut allergy has recently beenestimated at 1.3% in the general population. The increased use of peanutin food, very often in a masked form, perhaps explains this development.

Early sensitizations have been described in infants who have neverconsumed peanuts in conventional form, but who were apparentlysensitized in utero or via maternal milk, through maternalized milkshaving contained plant fats (peanut oil) or through medicinalpreparations in oily solution.

UTROGESTAN® may be prescribed in many cases of therapeutic indications,including as a supplement to the luteal phase during cycles of in vitrofertilization (IVF), and in the case of a danger of abortion or ofprevention of repeat abortion due to luteal insufficiency, up to the12th week of pregnancy. It is therefore possible, in theory, for afoetus to be exposed to UTROGESTAN® in utero.

To date, while the allergenic effects of peanut are definite, acontroversy still exists regarding the ability of peanut oil to engenderallergenic reactions. Many publications may be cited on this subject,including: Taylor et al., J. Allergy Clin. Immunol., vol. 68, p. 372(1981); Moneret-Vautrin et al., Pediatr. Allergy Immunol. vol. 5, p. 184(1994); Sabbah and Lauret, Allergie et Immunologie, vol. 26, p. 380(1994); de Montis et al., Arch. Pédiatr., vol. 2. p. 25 (1995)).

Given this fact, the applicant company devoted itself to developing anovel pharmaceutical composition, replacing the peanut oil with otheroils which do not have high risks of allergenicity, while at the sametime endeavouring to conserve the advantages of the prior formula.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the results of a comparative particle size studybetween UTROGESTAN® capsules (dashed line) and capsules described hereincontaining sunflower oil (solid line).

FIG. 2 illustrates the results of a comparative dissolution studybetween UTROGESTAN® capsules (♦) and capsules described hereincontaining sunflower oil (▪).

FIG. 3 illustrates the results of a bioequivalence study betweenUTROGESTAN® capsules (+) and capsules described herein containingsunflower oil (▪), with respect to mean plasma concentration (pg/ml).

FIG. 4 illustrates the results of a bioequivalence study betweenUTROGESTAN® capsules (+) and capsules described herein containingsunflower oil (▪), with respect to the natural log (Ln) of mean plasmaconcentration (pg/ml).

DETAILED DESCRIPTION

After much study and research, during which several plant oils weretested, sunflower oil, olive oil, sesame seed oil, colza oil and almondoil were selected. Specifically, the use of these oils makes it possibleto rule out the risks of allergic reactions, while at the same timeconserving all of the physicochemical and kinetic characteristics of theprior UTROGESTAN® formulation, characteristics which were the cause ofits success. Given that the method manufacturing the prior UTROGESTA®formulation on an industrial scale comprise steps which are verydelicate to carry out, it is to the credit of the applicant company tohave succeeded in modifying the formulation without increasing theproduction difficulties.

In the context of the present invention, the oils can be refined or not.A refined oil is an oil which is obtained from raw oil and which hasundergone a set of refining operations. The refined oil is a purifiedoil having a very low impurity content and especially devoid of highlyallergenizing proteins such as gluten.

In the pharmaceutical composition according to the invention, themicronized progesterone is preferably in suspension in sunflower oil,olive oil, sesame seed oil, colza oil, almond oil, or in a mixture ofsome or all these oils.

The applicant company is aware of U.S. Pat. No. 5,140,021 in the name ofGENESIS SYSTEMS CORPORATION (Maxson et al.) which describes a softcapsule containing a micronized progesterone in suspension in a highlyunsaturated oil. Sunflower oil appears among the oils cited in thispatent. However, the inventors of this patent U.S. Pat. No. 5,140,021have taken the greatest care to distinguish themselves from thepharmaceutical product UTROGESTAN®, i.e. the formulation developed andcurrently marketed by the applicant company, based on peanut oil. Thus,the micronized progesterone used in the GENESIS SYSTEMS patent isdescribed as having a particular particle size distribution which isdifferent from that used in UTROGESTAN®.

U.S. Pat. No. 5,140,021 only describes a laboratory scale preparation ofthe progesterone capsules and provides no teaching regarding thepreparation of capsules on an industrial scale. In addition, theprogesterone capsules according to said American patent do not containsoya bean lecithin, which is an essential element of the pharmaceuticalcomposition according to the present invention. Specifically, the soyabean lecithin plays the role of an agent for suspending the progesteroneparticles in the sunflower oil and of a lubricant during encapsulationof the content on an industrial scale.

The invention therefore relates to a pharmaceutical compositioncomprising micronized progesterone, soya bean lecithin and at least oneoil selected from the group consisting of sunflower oil, olive oil,sesame seed oil, colza oil and almond oil.

According to an advantageous embodiment of the pharmaceuticalcomposition according to the invention, the micronized progesterone isin suspension in oil or in a mixture of some or all these oils.

In the context of the present invention, the term “micronizedprogesterone” is intended to mean a progesterone in which at least 80%of the particles have a particle size of between 1 and 15 μm, preferably50% of the particles have a particle size of between 1 and 10 μm, andeven more preferentially 25% of the particles have a particle size ofbetween 1 and 5 μm, these particle sizes being measured using a laserparticle sizer of the Malvern type, by the procedure described in theexamples of the present patent application.

During the studies prior to choosing the oil, the applicant company wasable to observe, surprisingly and unexpectedly, that the combination ofsoya bean lecithin with the oils selected according to the invention wasvery advantageous since it did not modify the particle size of themicronized progesterone in suspension in the oil. In addition, nosignificant difference in the particle size distribution of themicronized progesterone in suspension became apparent between thecomposition based on peanut oil and that containing the oils used inaccordance with the invention.

With regard to the other oils tested, the particle size was not the samein the presence or absence of the soya bean lecithin. The main advantageof the oils selected according to the invention in physicochemical termscompared to the peanut oil is to simultaneously ensure:

comparable solubilities at saturation of the micronized progesterone;

comparable particle sizes of the suspension;

and comparable in vitro dissolution profiles.

Now, particle size and solubility at saturation significantly influencethe in vivo bioavailability of the progesterone.

The choice of these oils therefore makes it possible to have bettercontrol of the particle size distribution of the micronized progesteronein the oily suspension, and also the amount of progesterone solubilizedin the oil, and therefore to bring together all of the conditionsrequired for maintaining an in vivo bioavailability similar to thatobtained with UTROGESTAN®.

According to an advantageous embodiment of the pharmaceuticalcomposition according to the invention, the progesterone/oil(s) ratio isbetween 0.15/1 and 3/1, preferably between 0.25/1 and 2/1,preferentially between 0.40/1 and 1/1, and even more preferentially is0.67/1.

According to an advantageous embodiment of the pharmaceuticalcomposition of the invention, the soya bean lecithin/oil(s) ratio isbetween 0.005/1 and 0.3/1, preferably between 0.01/1 and 0.2/1,preferentially between 0.040/1 and 0.1/1, and even more preferentiallyis 0.067/1.

The pharmaceutical composition according to the invention may alsocomprise an oestrogen or an ester-type derivative thereof, preferablyselected from the group consisting of 17-β-oestradiol, oestrone,17-α-ethinyl oestradiol and oestradiol valerianate, or phyto-oestrogensand even more preferentially is 17-β-oestradiol.

The pharmaceutical composition according to the invention may be in theform, inter alia, of a soft capsule, of a hard capsule, of a tablet, ora drinkable suspension.

When the pharmaceutical composition according to the invention isintegrated into a pharmaceutical product, each dosage unitadvantageously comprises between 2 mg and 600 mg of micronizedprogesterone, preferably between 30 mg and 300 mg, and even morepreferentially between 100 mg and 200 mg.

The pharmaceutical composition according to the invention may beadministered orally or vaginally, depending on the therapeuticindications.

Vaginal administration also represents an alternative to oraladministration in the case of side effects due to the progesterone(drowsiness after oral absorption) or of contraindication to oraladministration (hepatopathy).

According to an advantageous embodiment of the pharmaceuticalcomposition according to the invention, the capsule comprises gelatin oran equivalent.

The invention also relates to a method for preparing a pharmaceuticalcomposition comprising micronized progesterone, soya bean lecithin, andat least one oil selected from the group consisting of sunflower oil,olive oil, sesame seed oil, colza oil and almond oil.

This method comprises the following successive steps:

-   -   mixing of oil(s) and of soya bean lecithin is carried out, with        stirring, in order to obtain a mixture;    -   the micronized progesterone is added, with stirring, to the        mixture thus obtained in order to obtain a homogeneous        suspension.

This suspension may be administered as such, in the form of a drinkablesuspension, or be presented in the form of soft capsules or hardcapsules, but may also be used to impregnate an absorbent supportpresented in the form of powder.

This absorbent support may be of the maltodextrin and/or derivatives,silica and/or derivatives, cyclodextrin and/or derivatives or cellulosepowder and/or derivatives type, or a combination thereof, or any otherpharmaceutical raw material which possesses equivalent properties.

The powder thus obtained may then be presented in the form of hardcapsules or tablets. The hard capsules or tablets containing the powdermay also comprise binding agents, disintegrating agents, diluents and/orlubricants.

The invention also relates to the use of the micronized progesterone, ofthe soya bean lecithin, and of at least one oil selected from the groupconsisting of sunflower oil, olive oil, sesame seed oil, colza oil andalmond oil in the preparation of a medicinal product for treating aphysiological condition linked to insufficiency of progesteronesecretion.

As examples of such physiological conditions, mention may be made of:luteal insufficiency, menstrual irregularity, premenstrual syndromes,mastodynia, benign mastopathies, premenopause, sterility due to lutealinsufficiency, disorders due to menopause, local contraception, forprevention of repeated abortions in the case of luteal insufficiency,danger of premature birth, acne, alopecia, for prevention ofosteoporosis, endometrial cancers and epilepsy.

The invention also relates to the use of the micronized progesterone, ofthe soya bean lecithin, and of at least one oil selected from the groupconsisting of sunflower oil, olive oil, sesame seed oil, colza oil andalmond oil and also of an oestrogen, in the preparation of a medicinalproduct for treating a physiological condition linked to insufficiencyof progesterone secretion. The oestrogen is preferably selected from thegroup consisting of 17-β-oestradiol, oestrone, 17-α-ethinyl oestradiol,oestradiol valerianate, or phyto-oestrogens and even more preferentiallyis 17-β-oestradiol.

The invention will be more clearly understood using the nonlimitingexamples described below.

EXAMPLE 1 Pharmaceutical Composition in the Form of a Soft CapsuleAccording to the Invention

The content of a soft capsule according to the invention is described inTable I below.

TABLE I Percentage formula References to Compound name (%) per unit (mg)Function standards Active substance Micronized 40.00 100.00 Active Ph.Eur. progesterone substance 3^(rd) ed. Excipients Oil or mixture 59.60149.00 Diluent Ph. Eur. of oils 3^(rd) Ed. according to the inventionSoya bean 0.40 1.00 Emulsifier USP 24, lecithin NF 19. p. 2471

The applicant company has also prepared 500 mg capsules which arehomothetic with the 250 mg capsules described above. Thus, the 500 mgcapsules contain 200 mg of micronized progesterone, 2 mg of soya beanlecithin, and as an example, 298 mg of sunflower oil.

EXAMPLE 2 Study of Solubility of Micronized Progesterone in Various Oils

In order to select the optimum oily vehicle to replace the peanut oil,while at the same time conserving the physicochemical properties of theprior formulation, the following plant oils were tested with regard tothe solubility of progesterone in these oils:

-   -   peanut oil    -   olive oil    -   sunflower oil    -   sunflower oil with a high oleic acid content    -   colza oil    -   almond oil    -   soya bean oil    -   sesame seed oil    -   corn oil

Standard solutions were prepared as follows:

concentrated solution: progesterone batch A0098 10 mg oil qs for 20 mldiluted solution: concentrated solution 1 ml tetrahydrofuran (THF) 10 mlacetonitrile qs for 20 ml magnetic stirring: 5 minutes.

The saturated solutions were then prepared as follows:

The saturated solutions in each oil were maintained for one hour withstirring at room temperature, and were then filtered on a nylon filtersyringe with a diameter of 25 mm, at 0.45 μm.

Saturated solutions were diluted 200-fold:

saturated solution: 0.5 ml THF: 50 ml acetonitrile qs for 100 ml

The results are given in Table II below:

TABLE II RELATIVE CONCENTRATION DIFFERENCE* ON AT SATURATION THECONCENTRATION OIL TESTED (mg/ml) AT SATURATION (%) Peanut oil 16.77 —Colza oil 18.14 +8.2% Sunflower oil 17.50 +4.4% Sunflower oil 8.29−50.6% with a high oleic acid content Olive oil 17.46 +4.1%

TABLE III RELATIVE CONCENTRATION DIFFERENCE* ON AT SATURATION THECONCENTRATION OIL TESTED (mg/ml) AT SATURATION (%) Peanut oil 18.80 —Almond oil 18.98 +1.0% Soya bean oil 16.19 −13.9% Sesame seed oil 19.80+5.3% Corn oil 15.60 −17.0% *Peanut oil = reference oil

The colza oil, sunflower, olive oil, sesame seed oil and almond oil wereselected following this study of solubility at saturation.

Among the various suppliers of oils mention may be made, by way ofexample, of:

-   -   for the olive oil: LESSIEUR;    -   for the sunflower oil: HENRY LAMOTTE.

EXAMPLE 3 Manufacturing of Soft Micronized Progesterone CapsulesAccording to the Invention

The manufacturing of soft capsules based on micronized progesteroneaccording to the invention is carried out as follows:

The capsules are prepared according to one of the methods known per seto those skilled in the art.

For a batch of 2 300 000 capsules, each containing 100 mg ofprogesterone, the following procedure is carried out:

The atmosphere is controlled at 22° C.±3° C. and at a relative humidityof 35%±10%.

The following ingredients are weighed:

Progesterone 230.00 kg Sunflower oil 342.70 kg Soya bean lecithin 2.30kg

A mixer with a volume of 600 litres is placed under vacuum.

Three quarters of the amount of sunflower oil is introduced under vacuuminto this mixer and the soya bean lecithin is added.

The mixer is again placed under vacuum (between 0.7 bar and 0.9 bar),followed by stirring at low speed between 10 rpm and 15 rpm.

The progesterone is added under vacuum, followed by the remainingquarter of sunflower oil, and the temperature is brought to 23° C.±3° C.

Next, vigorous stirring is carried out until homogenization is obtained.

The mixer with vigorous stirring is placed under a pressure up to amaximum of 1 bar.

Continuous sieving using a 500 μm sieve is carried out and the mixtureis transferred into a storage container.

The storage containers are placed under vacuum and then stirred atbetween 2400 and 2000 rpm for 15 minutes. They are again placed undervacuum and restirred for 30 minutes at a speed of between 2000 and 2500rpm.

The stirring is stopped and the containers are left to stand for 5minutes under vacuum.

The encapsulation is carried out in a conventional manner known to thoseskilled in the art.

EXAMPLE 4 Determination of the Particle Size of a Capsule According tothe Invention

A comparative particle size study was carried out between UTROGESTRAN®capsules and capsules according to the invention containing sunfloweroil.

The material used is as follows:

-   -   Mastersizer 2000 laser particle sizer    -   Hydro 2000 SM measuring cell        according to the following method:

Amount of sample per measurement: 1 or 2 drops deposited using a pipette

Medium: filtered saturated sunflower oil. This oil is prepared withmagnetic stirring, maintaining the temperature at 37° C., for 1 hour,and then filtered on filter paper.

-   -   Refractive index: (oil average) 1.4671    -   Medium volume: 100 ml

Stirring rate: 1800 rpm

Percentage obscuration: between 10 and 20%

Weighted residual percentage: <3%

Number of measurements per preparation: 2. The measurements begin afterthe percentage obscuration has been stable for 30 min.

The results given in FIG. 1 hereinafter demonstrate that the particlesizes of the two capsules are highly comparable.

Further studies carried out by the Applicant Company have shown that thesize distribution of progesterone in sesame seed oil, olive oil, colzaoil or almond oil, is also comparable to that obtained in peanut oil.

EXAMPLE 5 Comparative In Vitro Dissolution Study Between a UTROGESTRAN®Capsule and a Capsule According to the Invention

A SOTAX AT7 dissolution machine with rotating baskets was used.

20 mg of exactly weighed progesterone are dissolved in 2 ml of ethanol,in a 200 ml volumetric flask (class A), this is then treated withultrasound and the volume is made up to the capacity line using thedissolution medium (1% Kleptose).

The control solution is filtered on a fiberglass syringe filter with aporosity of 1 μm.

7 tanks are placed in a waterbath at constant temperature, and then 1000ml of dissolution medium are transferred into each of the 7 tanks.

1 capsule is placed in 6 tanks, and then the baskets are immersed in thedissolution medium at a distance of 25 Mm±2 Mm between the basket andthe bottom of the tank.

The baskets are stirred, and then a control solution is prepared.

At each time interval planned (5, 10, 15, 30, 45, 60, 90, 120, 150, 180,225, 270, 315 and 360 minutes), the samples are collected and thenanalysed by UV spectrophotometry (λ: 248 nm).

The results given in FIG. 2 hereinafter demonstrate that the in vitrodissolution curves for an UTROGESTAN® capsule and for a capsuleaccording to the invention containing sunflower oil are virtuallyidentical.

The physicochemical characteristics of the prior formulation aretherefore conserved in the formulation according to the invention.

EXAMPLE 6 Bioequivalence Study Between UTROGESTAN® Capsules and thePharmaceutical Composition According to the Invention

A bioequivalence study was carried out in order to compare capsulesaccording to the invention containing 100 mg progesterone in suspensionin sunflower oil with UTROGESTAN® capsules.

The study was carried out on a representative sample of 60 women, instarvation conditions.

The results of the study showed a bioequivalence between the capsulesaccording to the invention and UTROGESTAN® (see FIGS. 3 and 4thereafter).

1-10. (canceled)
 11. A pharmaceutical composition comprising: micronizedprogesterone, soy bean lecithin, and olive oil.
 12. The pharmaceuticalcomposition according to claim 11, wherein the progesterone/oil ratio isbetween 0.15/1 and 3/1.
 13. The pharmaceutical composition according toclaim 11, wherein the soy bean lecithin/oil ratio is between 0.005/1 and0.3/1.
 14. The pharmaceutical composition according to claim 11, furthercomprising an oestrogen or an ester-type derivative thereof.
 15. Thepharmaceutical composition according to claim 11, wherein at least theprogesterone is in suspension in the oil.
 16. The pharmaceuticalcomposition according to claim 11, in the form of a soft capsule. 17.The pharmaceutical composition according to claim 11, in unit dosageform comprising between 2 mg and 600 mg of micronized progesterone. 18.A method for preparing a pharmaceutical composition comprising thefollowing successive steps: mixing olive oil with soy bean lecithin inorder to obtain a mixture; and adding micronized progesterone to saidmixture to obtain a homogeneous suspension.
 19. A method for thetreatment of a physiological condition linked to insufficiency ofprogesterone secretion comprising the step of administering to thepatient a pharmaceutical composition comprising: micronizedprogesterone, soy bean lecithin, and olive oil.
 20. The method accordingto claim 19, in which the pharmaceutical composition further contains anoestrogen, or an ester-type derivative thereof.
 21. The pharmaceuticalcomposition according to claim 11, wherein the progesterone/oil ratio isbetween 0.25/1 and 2/1.
 22. The pharmaceutical composition according toclaim 11, wherein the progesterone/oil ratio is between 0.40/1 and 1/1.23. The pharmaceutical composition according to claim 11, wherein theprogesterone/oil ratio is 0.67/1.
 24. The pharmaceutical compositionaccording to claim 11, wherein the soy bean lecithin/oil ratio isbetween 0.01/1 and 0.2/1.
 25. The pharmaceutical composition accordingto claim 11, wherein the soy bean lecithin/oil ratio is between 0.040/1and 0.1/1.
 26. The pharmaceutical composition according to claim 11,wherein the soy bean lecithin/oil ratio is 0.067/1.
 27. Thepharmaceutical composition according to claim 14, wherein the oestrogen,or the ester-type derivative thereof is selected from the groupconsisting of 17-beta-oestradiol, oestrone, 17-alpha-ethinyl oestradioland oestradiol valerianate, or phyto-oestrogens.
 28. The pharmaceuticalcomposition according to claim 14, wherein the oestrogen, or theester-type derivative thereof is 17-beta-oestradiol.
 29. Thepharmaceutical composition according to claim 17, comprising between 30mg and 300 mg of micronized progesterone.
 30. The pharmaceuticalcomposition according to claim 17, comprising between 100 mg and 200 mgof micronized progesterone.
 31. The pharmaceutical composition accordingto claim 11, wherein at least 80% of the particles of said micronizedprogesterone have a particle size of between 1 and 15 μm.
 32. Thepharmaceutical composition according to claim 11, wherein 50% of theparticles of said micronized progesterone have a particle size ofbetween 1 and 10 μm.
 33. The pharmaceutical composition according toclaim 11, wherein 25% of the particles of said micronized progesteronehave a particle size of between 1 and 5 μm.
 34. The method according toclaim 20, wherein the oestrogen, or the ester-type derivative thereof isselected from the group consisting of 17-beta-oestradiol, oestrone,17-alpha-ethinyl oestradiol and oestradiol valerianate, orphyto-oestrogens.
 35. The method according to claim 20, wherein theoestrogen, or the ester-type derivative thereof is 17-beta-oestradiol.36. The method according to claim 19, wherein at least 80% of theparticles of said micronized progesterone have a particle size ofbetween 1 and 15 μm.
 37. The method according to claim 19, wherein 50%of the particles of said micronized progesterone have a particle size ofbetween 1 and 10 μm.
 38. The method according to claim 19, wherein 25%of the particles of said micronized progesterone have a particle size ofbetween 1 and 5 μm.